What is exercise induced collapse (EIC)?
Dogs affected with EIC can tolerate mild to moderate exercise, but 5 to 20 minutes of strenuous exercise with extreme excitement induces weakness and then collapse. Severely affected dogs may collapse whenever they are exercised to this extent – other dogs only exhibit collapse episodes sporadically.
The first thing noted during an episode is usually a rocking or forced gait. The rear limbs then become weak and unable to support weight. Many affected dogs will continue to run while dragging their back legs. Some of the dogs appear to be uncoordinated, especially in the rear limbs, with a wide-based, long, loose stride rather than the sort stiff strides typically associated with muscle weakness. In some dogs the rear limb collapse progresses to forelimb weakness and occasionally to a total inability to move. Some dogs appear to have a loss of balance and may fall over, particularly as they recover from complete collapse. Most collapsed dogs are totally conscious and alert, still trying to run and retrieve, but as many as 25% of affected dogs will appear stunned or disoriented during the episode.
Is EIC only a problem in Labrador retrievers from field trial lines?
No. We have identified the EIC gene at a high carrier rate (> 30%) in all Labrador lines tested: field trial, hunt test, conformation, pet and service.
Is EIC only a problem in Labrador retrievers?
No. Although EIC and the DNM1 gene mutation are quite common in Labrador Retrievers, we have also identified it in several other breeds, including Chesapeake Bay and Curly Coated Retrievers, Boykin Spaniels, Bouvier des Flanders, German Wirehaired Pointers Old English Sheepdogs, Cocker Spaniels and Pembroke Welsh Corgis. The full extent of breeds that may be affected by EIC is not yet known.
A similar condition has been identified in Border Collies. More information.
I have a collapsing border collie, Should I test them for EIC?
We have tested several dozen collapsing border collies for the EIC mutation. All have tested negative for the mutation this test detects.
Our collaborating researchers at the University of Saskatchewan have had the opportunity to evaluate several collapsing border collies. They have found that the presentation of this collapse is very different from that seen in EIC affected dogs.
We are now conducting a comprehensive physiological and genetic study to try to find the underlying basis for this Border Collie Collapse (BCC). Please see our research website for more details on BCC, and how you can participate.
Is EIC related to CNM?
CNM, or centronuclear myopathy, is also present in Labrador Retrievers. However, it is a completely different disease from EIC in both its clinical and physiological basis, and is due to a mutation in a different gene. It is theoretically possible that a dog could have only the CNM mutation, only the EIC mutation, or have both mutations. More information on CNM can be obtained from the LabradorCNM site.
At what age does EIC typically develop?
Even though a dog’s genetic susceptibility to EIC is determined by the combination of E or N forms of the EIC gene it obtains from its parents, signs of EIC do not typically develop until the dogs begin intense retriever training. First symptoms are usually noted between 5 months and 3 years of age. However, we have confirmed affected dogs who did not have collapse episodes until as late as age 10.
Does the ambient temperature or the body temperature play a role in EIC?
Dogs that collapse with EIC, as well as normal dogs after similar exercise, have a temperature of 106-108 F. We believe it is possible that the activity of the E form of the protein may be further diminished by the elevated body temperatures that usually develop during exercise itself. Evidence that DNM1 mutations cause temperature sensitive alterations in dynamin 1 function, resulting in neurological and neuromuscular defects are found in other organisms, including fruit flies (Drosophila melanogaster), and worms (C elegans). While dogs can collapse under any temperature and humidity conditions, it has been found that higher than normal temperature and humidity can make a collapsing event more likely to occur.
Genetics and breeding
What is EIC's mode of inheritance?
EIC is inherited in an autosomal recessive fashion. Every dog inherits either the N (normal) or the E (EIC mutant) form of the DNM1 gene from each parent.
N/N - Clear
E/N - Carrier
E/E - Affected
See Implications of the EIC Mutation for Breeding for diagrams of the different possible mating combinations.
How certain are you that you have found the EIC gene?
We performed a genetic linkage study to identify the chromosomal location of EIC gene. An examination of the inheritance pattern of DNA markers in multi-generation Labrador Retriever pedigrees where EIC was present eventually identified a small segment on canine chromosome 9 that must contain the EIC gene. An analysis with another type of DNA marker then further narrowed the region that must contain the EIC gene down to about a dozen genes.
We then sequenced the DNA of several of these genes that are involved in muscle and nerve metabolism and function. That is when a DNA sequence difference (i.e., a mutation) between EIC and control dogs in the DNM1 gene was identified.
A manuscript reporting these exciting results was published in the October 2008 issue of Nature Genetics, one of the most highly regarded journals of genetic research. The article can be found under the following citation: Patterson EE, Minor KM, Tchernatynskaia AV, Taylor SM, Shelton GD, and Mickelson JR. (2008). A canine dynamin 1 (DNM1) mutation is highly associated with the syndrome of exercise-induced collapse. Nature Genetics 40, 1235-1239.
More information on the discovery of the gene.
Is the EIC DNA test a marker test or a gene mutation test?
We are testing for a single DNA base pair change in a specific gene, the DNM1 gene; therefore this can be referred to as a gene mutation test. This situation is different from other types of genetic tests that describe only the identification of a DNA marker that could be very far away from the EIC gene, and not be as highly predictive of the true gene and mutation as desired. The results for this EIC mutation test will always be the same for samples provided from the same dog.
What is meant by saying that the DNM1 mutation is highly associated with EIC?
Scientists are always cautious in reporting conclusions regarding data to other scientists and to the public, and in so doing usually try not to state anything has a 100% certainty of being correct. However, the chances that the DNM1 mutation is not associated with EIC are less than 1 in a trillion as reported in our Nature Genetics article.
The role of DNM1 in nerve and muscle function clearly supports it being an extremely plausible EIC gene. A description of the precise effect of the DNM1 mutation on the function of the dynamin 1 protein remains before we can even more confidently state that the DNM1 mutation (i.e., E form of the this gene) is the causative EIC mutation.
In other words, in calling this DNM1 mutation highly associated with EIC, we are acknowledging that we have not yet proven this mutation to be causative by functional experiments, and are simply following a convention among scientists in reserving final judgment as to whether this mutation is the absolute genetic and physiological cause of EIC. There is also always a small statistical chance that another DNM1 gene mutation, in near-perfect linkage with the known DNM1 mutation, could be identified and prove to be the causative mutation.
What does the DNM1 gene do?
The DNM1 gene and its mutation are a compelling candidate gene and causal mutation for EIC due to the critical role of the dynamin 1 protein in synaptic communication between nerves in the central nervous system and between nerve and muscle at the neuromuscular junction.
Specifically, both nerve and neuromuscular synaptic transmission requires the fusion of small intracellular synaptic vesicles containing neurotransmitter with the nerve cell membrane. The neurotransmitters are then released and diffuse to the adjacent neuron or muscle fiber and trigger a response (either nerve signal propagation or muscle contraction).
The dynamin 1 protein normally functions to help reform new synaptic vesicles from the membrane. These reformed vesicles can again be filled with neurotransmitter to enable synaptic transmission to be sustained. Dynamin 1 is particularly critical to synaptic vesicle formation during times of high stimulation when synaptic vesicle use is very high.
We hypothesize that the mutated form of the dynamin protein will have diminished function, interrupting synaptic transmission during intense exercise, and causing the muscle-controlling nerves to not fire when directed to do so, resulting in lack of nerve and muscle control, and a collapse
How does the mutant DNM1 gene cause EIC?
The DNM1 gene produces a protein called dynamin 1 that functions in communication between neurons in the central nervous system, and between the motor neuron and the muscle fiber at the neuromuscular junction. It is known that mice with no functional DNM1 gene or dynamin 1 protein at all die soon after birth. Therefore, we hypothesize that the DNM1 gene mutation found in EIC susceptible dogs causes a somewhat diminished function (but not a complete lack of function) of the dynamin 1 protein in the brain and nerve fibers.
It is likely that carrier dogs, which would have both the E and the N forms of the dynamin 1 protein in their neurons, have enough functional dynamin 1 to ensure neural function in all situations. Even E/E dogs that produce only the E form of the protein function normally under non-stressful situations. This supports the idea that the EIC form of the protein works sufficiently well to enable normal nerve communication during mild to moderate activity.
However, we also hypothesize that in E/E dogs the activity of only the E form of the protein is not sufficient to deal with high activity levels that can occur, such as during strenuous exercise and intense excitement. This then is the precipitating event that causes the collapse.
My dog is E/E but to my knowledge has never collapsed.
To date we have identified over 800 dogs as E/E. More than 80% of all E/E dogs that are over age 3 have been observed to collapse. The remaining E/E dogs over age 3, and in particular younger E/E dogs may not yet have been exposed to sufficient conditions to initiate a collapse.
Besides excitement and exercise intensity, other factors affecting the likelihood of an E/E dog collapsing also appear to include the level of stress experienced in training in the different lines, including the use of e-collars and the difficulty of the retrieving event. The E/E dogs most commonly seen to experience EIC episodes also seem to have a very excitable temperament and lots of drive. More information on factors contributing to collapse.
We consider all E/E dogs genetically susceptible to EIC. However, like any genetic disease, calling EIC a simple autosomal recessive disease is not completely accurate, as it is possible that some E/E dogs may never exhibit signs of EIC.
Thus being E/E does not guarantee that an individual dog will show classic signs of EIC, but dogs with classic signs of EIC are E/E. We understand that this can be confusing, and lead some to hope that there is some other cause for EIC than this DNM1 mutation. Please note however, that we have seen several examples of non-collapsing E/E dogs producing affected offspring.
My dog collapses but is not E/E.
It is important to realize that there are many other potential causes of collapse with exercise, that are not EIC, and these disorders or events are not necessarily caused by genetics or an EIC gene. These other causes include, but are not limited to: heart disease, lung disease, heat stroke, malignant hyperthermia, myasthenia gravis; muscular diseases, including CNM; Addison’s disease, and other neurologic and metabolic diseases.
See the Canine Genetics Lab for more information on differentiating EIC from:
- Heat troke
- Malignant Hyperthermia
- A Mitochondrial Myopathy
Can my E/N dog have episodes of EIC?
In questionnaires from more than 3,500 Labrador retrievers, we have found no evidence for increased susceptibility to collapse in EN Labradors vs. NN Labradors. For this data, dogs collapsing before 4 years of age and dogs that had attained 4 years without evidence of collapse were included, but dogs younger than 4 years of age with no history of collapse were not included because they were less likely to have yet expressed the phenotype. 210/2271 (9.2%) NN Labrador retrievers and 102/1312 (7.8%) EN Labrador retrievers had reports of collapse. For comparison, 649/776 (83.6%) EE Labrador retrievers had reports of collapse.
A manuscript reporting these results was published in 2011 under the following citation:
Minor, K.M., Patterson, E.E., Keating, M.K., Gross, S.D., Ekenstedt, K.J., Taylor, S.M., Mickelson, J.R., 2011. Presence and impact of the exercise-induced collapse associated DNM1 mutation in Labrador retrievers and other breeds. The Veterinary Journal. doi:10.1016/j.tvjl.2011.06.022.
Should I only use N/N dogs for breeding to prevent the possibility of producing E/E pups?
Although using only N/N dogs would more rapidly remove the prospect of EIC from future generations, it is very likely not the best approach to dealing with this problem, and we do not recommend this approach. Many excellent dogs in all other respects are E/N or even E/E, and to breed entirely away from their lines would potentially lose many of their finest attributes that people have come to accept, demand, and cherish.
Our data to date indicate that only E/E dogs are documented to have exhibited the classic signs of EIC. There is no chance of producing an E/E puppy if it is known that at least one of the parents is N/N. A breeding program that utilizes E/N or even E/E dogs can be logically implemented by mating to N/N dogs and retaining E/N or N/N puppies for future breeding that also retain most or all of the other highly desired characteristics. In general, we recommend matings that produce fewer carrier (E/N) dogs in each successive generation.
Do puppies from 2 parents that have tested N/N need to be tested?
No. As long as there were absolutely no surprises or accidents with the breeding, or mix-ups with the puppies, only puppies that will be used for breeding need to be tested. However, we will not certify the status of untested pups.
Testing and result reporting
How are the test results reported?
A written report of results will be reported (via fax or email) within 14 business days of sample receipt. Results will only be released to the veterinarian and/or owner listed on the submission form unless 'The Authorization to Release Confidential Information' (PDF) form has been completed.
What sample types does the VDL accept for EIC testing?
How old does the dog have to be to be tested?
We can test dew claws from the removed tissue of newly whelped pups.
For blood sample testing, the dog should be old enough to have 1-3 ml of blood drawn by a veterinarian. Generally this is 5-6 weeks of age or older.
After a pup has been weaned (at least 24 hours), we can accept cheek swab samples. Ideally, pups should be isolated from the dam and littermates for 1 hour before swabbing.
Is there a list of clear dogs?
The VDL does not directly maintain a list of clear dogs. However, the Orthopedic Foundation for Animals (www.ofa.org) does host EIC data.
This list can be accessed at https://www.ofa.org/search.html. Go to the second scrollable column of the section labeled "Report Type," scroll down below the DNA subheading and click on Exercise Induced Collapse. Then click the "begin search" button at the bottom of the table.
Why doesn't the VDL maintain a list of clear dogs?
We believe it is important not to breed to a single test result, such as EIC clear status. Other important issues include hip, patella, elbow, eye, thyroid and heart health; as well as genetic status for inherited disease such as:
- Progressive Retinal Atrophy & Retinal Dysplasia
- Centro Nuclear Myopathy (CNM)
- Degenerative Myelopathy
- Glycogen Storage Disease Type IIIa
OFA provides a single interactive database that contains this information all in one place.
How do I report my dog's result to the OFA?
Owners must submit results themselves following the instructions below:
- Print your result report from the Veterinary Diagnostic Laboratory.
- Complete the Application for DNA Based Genetic Database form which can be found at https://www.ofa.org/pdf/dnaapp_bw.pdf.(PDF)
- Fax or mail the OFA application, along with your result report, with fee to the address below with a check made payable to OFA. The results will be uploaded to the OFA open database and will be published on the OFA website.
Orthopedic Foundation for Animals
2300 E Nifong Blvd
Columbia , MO 65201-3806
Or fax to 573-875-5073
Submission fee/individual - $15.00
A litter of 3 or more submitted together - $30.00 total
Kennel rate (5 or more individuals submitted as a group, owned/co-owned by the same person) - $7.50 each
Affected dogs at any age are no charge.
How do I read the OFA number key?
LR = Breed Code, in this case a Labrador Retriever
EIC = OFA Database
1001 = Ascending numerical identifier given to each animal with a breed evaluated as normal and given a number, in this case the 1001st Labrador Retriever to be given an EIC number
4 = The age in months when the testing was done, in this case 4 months
F = Sex
PI or VPI = Indicates that the animal has been permanently identified in the form of tattoo or microchip. If the dog is permanently identified AND the ID has been verified and signed off by the attending veterinarian, a suffix of VPI is applied. If the animals lacks permanent identification, a suffix of NOPI is applied.
BP = By Parentage (see http://www.offa.org/dnacbp.html)
CAR = Carrier